PROJECT SUMMARY Medical advances in the treatment of HIV/AIDS have significantly improved the life expectancy and quality of life of HIV-infected individuals. However, complications arising from HIV-1 infection, including cardiovascular disease and , can reduce the efficacy of anti-retroviral medications (HAART), reduce HAART adherence, and decrease quality of life among HIV-infected individuals. Thus, addressing modifiable risk factors, such as tobacco use, has become a critical priority. Unfortunately, HIV-infected individuals are three times more likely to use tobacco than those in the general population, but little is known about the mechanisms that underlie these high smoking rates. One plausible mechanism is that the cognitive enhancing effects of nicotine ameliorate neurocognitive deficits associated with HIV-1 infection. HIV-associated neurocognitive disorders (HANDs) In the general population, acute nicotine withdrawal (i.e., 24 to 72 hours following cessation) produces deficits in cognitive function that, in turn, predict smoking relapse. This will be the first study to test whether t he neurocognitive impairments associated with HIV-1 infection may be exacerbated during nicotine withdrawal and increase the probability of smoking relapse among HIV-infected smokers (HIV+), compared to HIV- uninfected smokers (HIV-). Specifically, we hypothesize that: (1) HIV+ smokers (vs. HIV- smokers) are more likely to experience cognitive deficits during nicotine abstinence; (2) HIV+ smokers (vs. HIV- smokers) are more likely to relapse to smoking following standard treatment; and (3) abstinence-induced cognitive deficits will predict relapse and will mediate the association of HIV status with relapse. To this end, adult treatment- seeking smokers (N=300; 150 HIV+ and 150 HIV-) will complete this 12-week study, which is divided into two phases: a pre-quit laboratory phase (weeks 0-2) and a treatment phase (weeks 3-12). Subjects will complete two laboratory sessions during the pre-quit phase: once following 24 hours of mandatory smoking abstinence and once while smoking-as-usual (order counterbalanced). A comprehensive cognitive task battery assessing memory, attention, and executive function will be administered during each laboratory session. During the treatment phase, all subjects will receive standard smoking cessation treatment, including counseling (weeks 3-8) and open-label transdermal nicotine (TN) patches (weeks 4-12). The primary outcomes are: 1) cognitive performance following 24-hours smoking abstinence (vs. smoking-as-usual) during the pre-quit phase; and 2) 7-day point-prevalence, biochemically-confirmed abstinence rates at the end-of-treatment (EOT) for the treatment phase. Our study design bridges the gap between laboratory and treatment studies by including a rigorous test of mechanisms associated with relapse. Characterizing cognitive deficits during early nicotine withdrawal that are unique to HIV+ smokers and that predict relapse may offer critical guidance toward developing population-specific smoking cessation treatments that target cognitive function in the hopes of improving smoking cessation outcomes to help sustain the health benefits of HAART.